The invention is in the field of diffuse optical tomography and stroke.
Victims of stroke caused by an ischemic event in the brain can benefit from treatment with recombinant tissue plasminogen activator, a thrombolytic drug, within three hours of the ischemic event. On the other hand, if the stroke is caused by a bleed instead of an ischemic event, thrombolytic drugs are contraindicated. Thus, a quick and efficient means of distinguishing an ischemic event from a bleed in a stroke victim would aid a health care provider in managing the treatment of stroke victims. Furthermore, treatment protocols need to be tailored to individual patients. Therefore, continuous monitoring of cerebral perfusion would enable the health care provider to more effectively guide treatment in a patient with a specific pathology.
Diffuse optical tomography (DOT) refers to various non-invasive methods of imaging different tissues of a body or organ. Generally, DOT relies on the emission of light from a light source into the body, then detecting the light scattered from various tissues of the body. For example, since light scattered by hemoglobin in blood differs from light scattered by other tissues, DOT has been applied to the imaging of blood within the body. In addition, because the absorption of light by deoxyhemoglobin is different from the absorption of light by oxyhemoglobin, DOT has been used to locate areas of high or low oxygenation in the body by determining decreases or increases in the intensity of scattered light. However, the application of DOT in various imaging scenarios in the clinic has been limited by the inability to detect light scattered by deep tissues. This can be due to either the inability of the emitted light to reach deep tissues, or the inability to detect and measure the weak intensity of light scattered by the deep tissues (i.e., no measurable contrast between scattered light and background).
The invention is based on the recognition that ischemic events deep in the brain can be detected using DOT to monitor collateral blood flow abnormalities in cortical regions of the brain arising from the deep ischemic events using blood-borne tracer dyes (also called contrast agents or tracers). By extrapolating information from the cortical regions, deep ischemic events as well as cortical ischemic events in the brain can be monitored even if the light used for DOT does not penetrate into the deep portions of the brain, or if the contrast in the light scattered from blood and solid tissues in the deep portions of the brain is not easily detected.
The invention is also based on the recognition that a brain bleed can be imaged by DOT using a blood-borne tracer dye and detecting a localized region of a lower concentration of dye or of no dye at all, as compared to an adjacent region in the brain. The imaging of a brain bleed is made possible by recognizing that blood vessel constriction and clotting at the site of the bleed will inhibit the dye from infiltrating the region of the bleed while adjacent regions are unaffected. In addition, the use of a tracer dye increases the contrast in light scattered by blood versus solid tissue deep in the brain, thereby allowing blood volume to be imaged even where the intensity of scattered light is weak.
Accordingly, the invention features a method of detecting an ischemic event in a brain in a subject, using a first criterion, by (1) administering a dye bolus into the bloodstream of the subject; (2) directing light into the brain of the subject; (3) detecting light emitted from the brain over time at a detection location, the dye being present in the brain for at least a portion of the detection time, and the light emitted from the brain in the presence of the dye being different from the light emitted from the brain in the absence of the dye, the magnitude of the difference corresponding to the concentration of the dye; (3) establishing a reference time period corresponding to the time a peak concentration of a dye bolus takes to reach the detection location in a normal brain; (4) determining a subject time period corresponding to the time a peak concentration of the dye bolus takes to reach the detection location in the subject; and (5) comparing the subject time period with the reference time period, where a subject time period 1 or more seconds longer than the reference time period indicates an ischemic event in the brain. If the subject time period is 2 or more seconds longer than the reference time period, then an ischemic event in a deep portion of the brain is indicated.
In another aspect, the invention includes a method of detecting an ischemic event in a brain in a subject, using a second criterion, by (1) administering a dye bolus into the bloodstream of the subject; (2) directing light into the brain of the subject; (3) detecting light emitted from the brain over time at a detection location, the dye being present in the brain for at least a portion of the detection time, and the light emitted from the brain in the presence of dye being different from the light emitted from the brain in the absence of the dye, the magnitude of the difference corresponding to the concentration of the dye; (4) establishing a peak reference concentration of a dye bolus administered to a subject with a normal brain at the detection location; (5) determining a peak subject concentration of the dye bolus at the detection location; and (6) comparing the peak subject concentration with the peak reference concentration, where a peak subject concentration below the peak reference concentration indicates an ischemic event in the brain. If the peak subject concentration is below the peak reference concentration but at least 50% of the peak reference concentration, then an ischemic event in a deep portion of the brain is indicated.
The invention also includes a method of detecting an ischemic event in a brain in a subject, using a third criterion, by (1) administering a dye bolus into the bloodstream of the subject; (2) directing light into the brain of the subject; (3) detecting light emitted from the brain over time at a detection location, the dye being present in the brain for at least a portion of the detection time, and the light emitted from the brain in the presence of dye being different from the light emitted from the brain in the absence of the dye, the magnitude of the difference corresponding to the concentration of the dye; (4) establishing a reference time period corresponding to the time for the concentration of a dye bolus to vary from a threshold (e.g., 10, 5, 2, or 1% by volume) concentration to a peak concentration and back to the threshold concentration at the detection location in a normal brain; (5) determining a subject time period corresponding to the time for the concentration of the dye to vary from the threshold concentration to a peak concentration and back to the threshold concentration at the detection location; and (6) comparing the subject time period with the reference time period, where a subject time period longer than the reference time period indicates an ischemic event in the brain. If the subject time period is at least 2 seconds longer than the reference time period, then an ischemic event in a deep portion of the brain is indicated.
In still another aspect, the invention includes a method of detecting an ischemic event in a brain in a subject, using a fourth criterion, by (1) administering a dye bolus into the bloodstream of a subject; (2) directing light into the brain of the subject; (3) detecting light emitted from the brain over time at a detection location, the dye being present in the brain for at least a portion of the detection time, and the light emitted from the brain in the presence of the dye being different from the light emitted from the brain in the absence of the dye, the magnitude of the difference corresponding to the concentration of the dye; (4) establishing a reference map of cortical blood flow in a normal brain; (5) obtaining a subject map of cortical blood flow in the subject; and (6) comparing the reference map with the subject map, where a continuous region of decreased blood flow in the subject map, compared to the reference map indicates an ischemic event in the brain. If the continuous region of decreased blood flow is at least 20 mm at the longest diameter, then an ischemic event in a deep portion of the brain is indicated. In addition, this method can further include (7) comparing the position of the region of decreased blood flow with a map of known brain vasculature; and (8) extrapolating the position of the ischemic event in the brain of the subject.
In addition, the invention includes a method of detecting an ischemic event in a brain in a subject using any combination (e.g., all) of the criteria specified above. The methods described above also need not specify all the steps; only the last comparing step is required.
The invention further includes a method of detecting a brain bleed in a subject by (1) administering a dye into the bloodstream of the subject; (2) directing light from a light source into the brain of the subject; (3) detecting light emitted from the brain while the dye is present in a portion of the brain, the light emitted from the brain in the presence of the dye being different from the light emitted from the brain in the absence of the dye, the magnitude of the difference corresponding to the concentration of the dye, and the detecting step being performed while the dye is detectable in the blood circulation of the subject; and (4) determining the concentration of the dye in the portion of the brain, where a region of the portion with a lower concentration of the dye than an adjacent region of the portion indicates a brain bleed.
In another aspect, the invention includes a method of detecting a brain bleed in a subject by administering a dye into the bloodstream of the subject; (2) directing light from a light source into the brain of the subject; (3) detecting light emitted from the brain while the dye is present in a portion of the brain, the light emitted from the brain in the presence of the dye being different from the light emitted from the brain in the absence of the dye, the magnitude of the difference corresponding to the concentration of the dye, and the detecting step being performed after the initial dye concentration in the blood circulation of the subject has been reduced; and (4) determining the concentration of the dye in the portion of the brain, where a region of the portion with a higher concentration of the dye than an adjacent region of the portion indicates a brain bleed.
In the methods of the invention, the dye can be indocyanine green or any other suitable dye described herein, the difference in light can be the amplitude of light, and the subject can be a mammal (e.g., a human). In addition, the methods can include directing light into the brain through the scalp of the subject from a plurality of light sources and detecting light emitted from the brain using a plurality of photodetectors (e.g., charged-coupled devices).
In the methods, light can be emitted and detected using a system including (1) at least two optical sources which during operation emit light into a sample at spatially separated locations; (2) at least two optical detectors positioned to receive light emitted from the sample at spatially separated locations in response to the light emitted from the sources, wherein the signal g(i,j) produced by the jth detector in response to the optical radiation from the ith source can be expressed as g(i,j)=SiDjf(i,j), wheref(i,j) depends only on the properties of the head of the subject, Si is a coupling coefficient for the ith source, and Dj is a coupling coefficient for the jth detector; and (3) an analyzer which during operation calculates the value of the product SlDk for at least one of the source-detector pairs based on the signals produced by the detectors and simulated values of f(i,j) corresponding to a model of the optical properties of the sample.
Further, the light can be directed by at least two optical sources and detected by at least two optical detectors, the sources coupling light into the brain at spatially separated locations, and the detectors positioned to receive light emitted from the sample at spatially separated locations and generating signals in response to the light from the sources. In such a situation, the method can further include (1) providing the signals generated by the detectors, wherein the signal g(i,j) generated by the jth detector in response to the optical radiation from the ith source can be expressed as g(i,j)=SiDjf(i,j), where f(i,j) depends only on the properties of the sample, Si is a coupling coefficient for the ith source, and Dj is a coupling coefficient the jth detector; and (2) calculating the value of the product SlDk for at least one of the source-detector pairs based on the signals generated by the detectors and simulated values of f(i,j) corresponding to a model of the optical properties of the brain.
A xe2x80x9cnormalxe2x80x9d brain or region of a brain as used herein is a brain or region suitable to serve as a control or reference tissue for testing of potentially affected tissue in a subject brain. Thus, a normal or reference brain or region can be a different brain than that of the brain of a subject under DOT examination, or the same brain as that of the subject. Where the normal brain is the same as the subject""s, the control or reference tissue can be a matched, symmetric region (e.g., right versus left hemisphere), or a region adjacent to the potentially affected tissue. Due to calibration considerations (discussed below), regions adjacent to the potentially affected tissue serve as better normal portions of the brain than symmetric regions, which in turn are better normal portions than regions of a different brain in a different individual.
A xe2x80x9cdeepxe2x80x9d portion or region of a brain is greater than 1 cm below the inner surface of the skull.
The methods of the invention provide for a quick, non-invasive means of detecting and distinguishing a bleed or ischemic event in the brain of a stroke patient or suspected stroke patient. The methods are particularly applicable for a patient exhibiting a recent onset of one or more symptoms of stroke. In such a patient, distinguishing a bleed from an ischemic event in the shortest amount of time is important for determining the optimal treatment for the patient during the critical first few hours after an ischemic stroke. In addition, the methods can be applied continuously to monitor the development of a stroke in a patient for fine tuning of the treatment.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although suitable methods and materials for the practice or testing of the present invention are described below, other methods and materials similar or equivalent to those described herein, which are well known in the art, can also be used. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.